The goal of the proposed research is to investigate the role of Hsp90 in regulating amyloid generation associated with AD progression. Utilizing this knowledge, my long-term research goal is to understand the molecular mechanisms of disease progression in AD and search for therapeutic tools. A five-year research and training plan has been developed to meet these goals. This plan consists of training in animal pathology and behavior involved in AD progression. This plan will be implemented under the mentorship of the primary mentor, an expert in neuroscience research and neurodegeneration, and a co-mentor, an expert in Hsp90 biological function and Hsp90 inhibitor chemistry. The training will be supplemented by an expert in AD pathology and an expert in electrophysiology. The training will consist of structured readings, attendance at course lectures and seminars, structured laboratory experience and presentations at academic meetings. With complete support from my lab head and the university vice president, I will have access to a fully equipped laboratory of molecular and cellular neuroscience. The proposed research will test the hypothesis that the dysregulated cellular events occurring in AD development are dependent on Hsp90 for disease progression. Specific aims will: 1) characterize Hsp90-APP interaction and its regulation of A2 formation; 2) investigate Hsp90-regulated APP metabolism; and 3) the therapeutic effects of Hsp90 inhibitor on the pathology and electrophysiology abnormality of AD model mice.